Throughout this application various publications are referenced. The disclosures of these publications in their entireties are hereby incorporated by reference into this application in order to describe more fully the state of the art to which this invention pertains.
The invention relates to a method for enhancing an immune response by administering an immunostimulatory nucleotide sequence prior to antigen exposure. More particularly, the method is suited for enhancing antibody production, IFNxcex3 release, CTL activity and Th1-related effects in response to antigen administration.
Adjuvants are typically administered in conjunction with antigen in vaccination protocols. Adjuvants serve to amplify or modulate the immune response to a co-delivered antigen. Currently, few adjuvants (e.g., alum and MF59) have been approved for use in human vaccination.
Immunostimulatory DNA sequences (ISS) delivered in conjunction with an antigen activate innate immunity and bias the adaptive immune response toward Th1 differentiation. ISS have been used as an adjuvant to amplify the immune response to a co-delivered antigen. See, for example, WO 98/16247, and U.S. Pat. No. 5,736,524 and No. 5,780,448.
There remains a need for optimization of the nature and efficacy of vaccination and immunotherapeutic protocols.
The invention provides a method for enhancing an immune response to a substance, such as an antigen administered to a subject, or a pathogen to which the subject is exposed. The method can be used to modulate the magnitude, the duration, and the nature of the immune response to subsequent exposure to a substance. The method comprises administering an immunostimulatory nucleotide sequence (ISS) to the subject at least one hour prior to exposure to the substance by the subject. This xe2x80x9cpre-primingxe2x80x9d of the subject with ISS prior to antigen administration or pathogen exposure results in amplification of the Th1 immune response to the substance as compared to co-administration of ISS and antigen. Pre-priming with ISS also shifts the nature of the immune response from a Th2 type response to a Th1 type response.
Examples of an immune response that can be enhanced by the method of the invention include, but are not limited to, activation of innate immunity (e.g., macrophages, natural killer (NK) cells), a Th1 response, a cytotoxic T lymphocyte (CTL) response, and production of an antibody. The antibody response is preferably increased production of antibodies of the IgG2a subclass. The method can be used for immunizing a subject against an antigen, and provides more effective immunization than if the ISS were co-administered with the antigen. The method can be used prophylactically or therapeutically.
In preferred embodiments, the ISS comprises a CG, p(GC) or p(IC) DNA or RNA nucleotide sequence. Of these, a CG containing nucleotide sequence is preferred. Preferably, the ISS further comprises a pG nucleotide sequence. Examples of an ISS include, but are not limited to, sequences comprising 5xe2x80x2-rrcgyy-3xe2x80x2 (SEQ ID NO: 1), such as AACGTT, AGCGTC, AGCGTT, GACGTT, GGCGTT, AACGTC, and AGCGTC (SEQ ID NOs: 5-11, respectively), 5xe2x80x2-rycgyy-3xe2x80x2 (SEQ ID NO: 2) such as GTCGTT (SEQ ID NO: 24), 5xe2x80x2-rrcgyycg-3xe2x80x2 (SEQ ID NO: 3), or 5xe2x80x2-rycgyycg-3xe2x80x2 (SEQ ID NO: 4).
The ISS is preferably administered between about 6 hours and about 6 weeks prior to antigen administration, and more preferably between about 1 day and about 4 weeks prior to antigen administration. Most preferably, the ISS is administered between about 3 days and about 8 days prior to antigen administration. In a preferred embodiment of the method, the ISS is administered via a systemic route such as a dermal or intramuscular route, or via a mucosal route such as an intranasal, ophthalmic, intrarectal, intravaginal or intratracheal route.
Because pre-priming activates innate immunity, the method of the invention can be used to protect against subsequent infection by a pathogen, such as a viral, bacterial, parasitic or other infectious agent. Preferably, the substance is a pathogen or an antigen associated with an infectious disease, an allergen or a cancer. Examples of infectious disease include, but are not limited to, viral, bacterial, mycobacterial and parasitic disease.